National Academies Press: OpenBook
Suggested Citation:"Front Matter." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Suggested Citation:"Front Matter." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Suggested Citation:"Front Matter." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Suggested Citation:"Front Matter." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Suggested Citation:"Front Matter." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Suggested Citation:"Front Matter." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Page viii Cite
Suggested Citation:"Front Matter." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Suggested Citation:"Front Matter." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Suggested Citation:"Front Matter." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Suggested Citation:"Front Matter." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

HUMAN HEALTH RISKS WITH THE ,, SUBTHERAPEUTI C USE OF PENICILLIN OR TETRACYCLINES IN ANIMAL FEED Committee on Human Health Risk Assessment of Using Subtherapeutic Antibiot ics in Animal Feeds INSTITUTE OF MEDI CINE Divis ion o f Health Promot ion and Disease Prevent ion NATIONAL ACADEMY PRESS Washington , D . C . 1 989

$I­ C1g .A5 148 1'i€P NOTICE: The project that is the subject of this report was ( I approved by the Governing Board of the Nat ional Research Counc i l , whose members are drawn from the counc i l s of the National Academy of Sciences , the National Academy of Engineering , and the I nstitute of Medicine . The members o f the committee respons ible for the report were chosen for their special competenc ies and with regard for appropriate bal ance . Thi s report has been reviewed by a group other than the authors according to procedures approved by the Report Review Committee . The I nstitute of Medic ine was chartered in 1970 by the Nat ional Academy of Sciences to enl ist dist ingu ished members of appropriate profess ions in the examination of pol icy matters pertaining to the health of the publ ic . In thi s , the I nstitute acts under both the Academy ' s 1863 congress ional charter responsibil ity to be an advi ser to the federal government and its own initiative in ident ifying i ssues o f medical care , research , and educat ion . Thi s study i s supported by the Food and Drug Admini strat ion under contract 2 2 3-87-8047. The project off i cers are Mary Frances Lowe and Paul Lepore . Ava i l able From: Nat ional Academy Press 2 10 1 Constitution Avenue , N . W . Washington , D . C . 204 18 (supply l imited ) Institute o f Medicine 2 1 0 1 Const itut ion Avenue , N . W . Washington , D . C . 2 04 18 ( 2 0 2 )334-235 2 IOM-88-89

PREFACE In 1980 , at the request of the Food and Drug Administration ( FDA ) , a committee of the Assembly of Li fe Sciences of the National Research Council ( NRC ) prepared a report evaluating the effects on human health o f the use o f penicil l in and two tetracyclines (chlortetracycline and oxytetracycline) at subtherapeutic concentrations 1 in an imal feed . That committee concluded that the postulated ha z a rds to human hea lth from such use of antimicrobi a l s had been neither proved nor disproved . I t drew the conclus ion largely because a direct detailed epidemiologic invest igat ion o f the ha zards had not been feasible and in part because it was impossible to ascertain prior antimicrobia l exposures of individual animal sources o f meat products for human consumption . The committee recommended various epidemiologic studies ( especial ly of human il lness due to salmonel l ae and pathogenic Escherichia QQ!i ) and monitoring and surveil lance of the occurrence of antimicrobial resistance of enteric bacteria in humans , anima l s , and foodstuffs . Several years l ater , in 1987 , FDA asked the Institute o f Medicine t o conduct a n independent review o f the human hea lth consequences and the risk associated with the use of penic i l l in and the tetracycl ines at subtherapeutic concentrations in animal feed . The Institute established a committee and gave it a tightly drawn charge: specifical ly , to perform " a quantitative risk assessment " o f those consequences--to " assess the adequacy of existing human health data and use such data to arrive at an estimate o f 1 The Center for Veterinary Medicine cons iders any extended use of antibiotics in feed at 2 0 0 gjton or less beyond 2 weeks as " subtherapeutic use , " whether it i s for growth enhancement or disease prevention . "Use level s are general l y 2 0 0 g or less o f penici l lin or tetracycline per ton of feed , but dosage units wil l vary by species . Level s approved for qrowth cla ims and di sease prophylax i s are usua l ly l ower than those approved for disease treatment; however , there is some overl ap in the c laims for dose level s of 2 00 q per ton or less . " There is more concern in the agency "with the lenqth of time the ant ibiot ic is used in feed than in the level of druq . " (FDA personal correspondence , April 26, 1988 ) iii

risk , the bas is of which wil l be justified . " If complete quantification of human health risks was not possible because of inadequacies of the avail able data , the committee was to eva luate the scientific information that had become available s ince the 1980 report and make judgments about the magnitude of the risks . The committee has not addressed risk management , nor any aspects related to pol icymaking because thi s was not part of its charge . I n its risk assessment , the committee was to address the fol l owing questions: o Does the subtherapeutic use of penicil lin and the tetracyclines in anima l feed result in an increased frequency of antimicrobial resistance in pathogens , particul arly foodborne pathogens? I f so , can the increase in frequency be rel iably est imated and compared with the increases assoc iated with other sources of resistance? o Does antimicrobia l res istance increase (or dim inish) the abi l ity of foodborne pathogens to cause disease , change the number of foodborne pathogens (dose ) needed to produce disea se , or a l ter the severity of disease caused by foodborne pathogens? o Does the subtherapeutic use of penici l l in and the tetracycl ines in animal feed result in increased prevalence of pathogens in the anima l s so fed and in foods derived from them? o Does antibiotic resistance attributable to subtherapeutic use in feed increase the incidence o f foodborne in fect ious disease in humans or compl icate its medical management? The current committee i s wel l aware o f the longstanding uncertainty o f the benefits o f the subtherapeut ic use o f antimicrobial s i n anima l feed and its possible restriction in this country and abroad , and it understands the need for a risk assessment as a foundation for risk management in FDA's decision-making (rule-making ) regarding the use of feed addit ives . I t is inherently dif ficul t to rel ate human morbidity and mortal ity associated with a specific antibiotic-resistant bacterial pathogen directly to that pathogen's origin in l ivestock (or poultry ) on a farm or in a feedlot and to administration o f subtherapeutic amounts (as opposed to treatment amounts ) o f penicil lin and the tetracyclines to the anima l s . Unequivoca l direct evidence l inking morta lity to the postul ated initia l events is not ava i l able--certa inly not in su f f i c ient quant ity to establ ish a cause-and-effect relationship . For want o f direct evidence , the committee has iv

approached its task indirectly by developing a risk model , using the most reliable data avail able for the individua l elements involved , including annual numbers o f reported cases of specified infections , fractions of cases due to bacterial strains that show antibiotic resistance , mortality rates , fractions of deaths associated with bacterial stra ins of farm origin , and fractions of antibiotic-resistant strains of farm origin caused by subtherapeutic use of antibiotics in animal feed . Although some bacterial pathogens (salmonel l ae , Campyl obacter jejuni , enterohemorrhagic E· coli , and Yersin ia enterocolitica ) are commonly foodborne and of animal origin , salmonel l a infections are the only ones that have been reportable for many years and for which incidence figures and antimicrobial-susceptibility data have been col lected . Sa lmonel losis has therefore been selected for the risk assessment model , a lthough we acknowledge that several other human infections would a l so be relevant to our charge . The committee is particularly conscious o f the l imitations and inherent weaknesses of the data ba se used in the risk assessment model . Where an assumption or est imate had to be made , we have stated its basis . We are aware that some estimates used in the model are weaker than others : for example , the fraction of antibiotic-resistant strains of farm origin attributable to subtherapeutic use of antibiotics (or penicil lin and the tetracyclines specifica l l y ) . Because some data for the model were only estimates , we considered a range o f values (low , mid-range , and high ) for each element and expressed the final risk estimates (deaths per year ) a s min imum , median , and maximum . In addition to the risk assessment , the committee has reviewed further new informat ion pert inent to human hea lth that might be rel ated to subtherapeutic use of antibiotics in anima l feed . Some of the new in formation addresses study possibilities identified by the former NRC committee on subtherapeutic antibiotic use in animal feeds . Some of it deals with the biologic impact of antibiotic resistance in bacteria and the use of molecular biologic techniques in identifying clonal features of isolates obtained from farm animal s , from foodstuffs derived from livestock and farm animal s , and from infected humans . Some of it reflects fol l owup experience in European countries that have , in the l ast 10-20 years , by regulatory action prohibited use in animal feed of subtherapeut ic concentrat ions o f antibiotics that are used in treatment of humans . Much o f this information provides only circumstantial ev idence bearing on the question under consideration . Some of the facts even appear to be mutual ly contradictory . The committee has not addressed any cost-benefit aspects of the issues rel ated to this problem , nor has it made any recommendations regarding regul atory strategies or policies . I t hopes that its report on the subtherapeutic use o f v

penicil lin and the tetracyclines in animal feed wil l be useful to FDA in its consideration of the risk involved and appropriate risk management . The committee stresses the continuing need for more extensive gathering of detail ed epidemiologic information to define the human health risks more sharply . vi

COMMITTEE ON HUMAN HEALTH RISK ASSESSMENT OF US ING SUBTHERAPEUTIC ANTIBIOTICS IN ANIMAL FEEDS Morton N . swartz , Chairman Institute of Medicine Harvard Medical School Sta f f : Massachusetts General Hos pi t al Boston , MA 0 2 1 14 Enriqueta c. Bond James A . Fra z ier John c . Ba ilar I I I Linda DePugh McG i l l univers ity Montreal , PQ , Canada Michael Barza New England Medical Center Tufts University School for Medicine Bos t on , MA 0 2 1 1 1 Theodore Eickhoff Univers ity of Colorado S chool of Medicine Presbyterian/ Sa int Luke ' s Medica l Center Denver , co 802 03 Barry I . E isenste in Univers ity of Michigan Medical School Ann Arbor , MI 48109 Richard Hornick University of Florida Med ic a l S chool Orl ando Reg i on a l Medical Center Orl ando , FL 32 806 Dori s Mi l ler C ol l ege of Veterinary Medic ine Univers ity of Ge o rgi a Athens , GA 30602 Thomas F . O ' Brien Harvard Medica l S chool B ri gham and Women ' s Hospita l Boston , MA 02115 Joseph Rodricks Env iron Co rp o ra t i o n Wash i ngt on , D . c . 2 0 0 07 vii

ACKNOWLEDGMENTS The committee is grate ful to the numerous individual s and organi z at ions that have contributed in formation used i n the preparation o f this report . We acknowledge Gerald B . Guest , Larry Rol l ins , and Phi l ip Frappaolo of the Food and Drug Administrat ion ; Harry Rosenberg and Diane Wagener of the National Center for Health Stat istics ; and Paul A . Blake , Mitche l l L . Cohen , Scott D . Holmberg , Wi l l iam Martone , and Robert V . Tauxe o f the Centers for Disease control . Severa l persons helped cons iderably by part i c ipating in one o f the committee ' s meet ings and d iscussing selected topics of interest : Edward H . Kass ( who was on the former NRC committee on thi s subject ) , George w. Beran , Stuart Levy , Jerry Brunton , and members of the Anima l Health Inst itute ' s Industry Pane l --Richard Bowen , Dianne Fagerberg , Richard Gusta fson , Virg i l Hays , and Harry Jamison . We also acknowledge the assistance provided by many persons in scient i f i c and trade organ i z at ions : Bruce Lev in , Univers ity o f Massachusetts ; Rol f Freter , Univers ity o f Mich igan ; Lucy Tompkins , Stanford Univers ity ; Frank Lowe , Tufts Univers ity School of Veterinary Medic ine ; Joe s. Gl oyd , American Veter inary Medical Association ; D . Jewel l and Judith J . Putnam , u.s. Department of Agricul ture ; David Meeker , Nat ional Pork Producers Counc i l ; Darrel l Wilkes , National Cattleman ' s Association ; Burt Rutherford , Texas Cattl e Feeders Association ; J . Stephen Pretanik , Nat iona l Broiler counc i l ; Lee Boyd , American Feed I ndustry Association ; E l l a Bl anton , u . s . Animal Health Associat i on; Robert Zimbl e , Society for Animal Science ; Stephan G . Thayer , Poultry Disease Research Center ; Kathleen Ferris , Nat ional Veterinary Services Laboratory ; Cra ig N . Carter , Texas Veterinary Medical Diagnostic Laboratory ; John R . Col e , Jr . , Ti fton Veterinary Diagnostic Laboratory ; Wil fred T . Spr inger , Loui s iana Agricultural Experiment Stat ion ; Mel issa c. L ibal , An imal Disease Research and Diagnostic Laboratory ; Roger Sal ine , North Carol ina State Univers ity ; David French , Univers ity o f Georgia ; Al Leman , Swine Graphics ; John Donahoe , Arbor Acres Farm , Inc . ; Y . Gha z ikhamian , Nicho l a s Breeders ; Ken swartz , Story C ity , I owa , and Roy curt i s s I I I , Wash ington Univers ity . The assistance to Dr . Rodricks g iven by Mr . Mark Corrales and Mr . Marc Atayi at Environ Corporat ion in ix

computer formulations of the risk model is qrate ful ly acknowledqed . The committee is qrateful , in addition , to investiqators from abroad who kindly furnished information on the ir experience with antimicrobial res istance in enteric orqanisms in the ir countries durinq periods of unrestricted and restricted subtherapeutic use of antibiotics : John R . Wal ton , David Pearson , and Bernard Rowe of the United Kinqdom : P . A . M . Guinee o f the Netherlands : and o. M . McLean o f British Columbia . Final ly , the committee thanks the staf f for their assistance in preparinq this report : Enriqueta c . Bond , James A . Fra z ier , Wal ly Waterfa l l , Linda OePuqh , and Judy Tiqer of the Institute of Medicine , and Chuck M . Benbrook o f the Board o n Aqriculture . X

CONTENTS I EXECUTIVE SUMMARY 1 II INTRODUCTION 12 Historical Background , 1 3 Committee Approach , 1 4 The Report , 16 III BIOLOGIC IMPACT OF RESISTANCE TO ANTIMICROBIAL 20 AGENTS Brief History of Cl inical Development of Drug Res istance , 2 0 Mechanisms o f Acquiring Antimicrob ial Res istance in Bacteria , 2 1 Role o f Antimicrobial Dosage in Selection o f Drug-Resistant Bacterial Populations , 2 6 Spec i fic Mechanisms of Res istance t o Antimicrobial Drugs in Pathogens from Animal Sources , 3 4 E f fects o f Res istance to Antimicrobial Drugs on Bacterial Virulence , 3 6 Summary o f the Biologic Impact o f Drug Res istance , 4 4 IV QUANTIFICATION OF ANTIBACTERIAL AGENTS USED IN 59 LIVESTOCK AND POULTRY FEEDS Population of Livestock and Poulty , 59 Animal Consumption of Feed and Bacterial Content o f Gastrointestina l Waste , 6 1 Total Antibiotic Production , 6 1 Ant ibiot ic Use in Farm and Feedlots , 6 8 Subtherapeutic Use o f Antibacterial Drugs I n Animal Feed , 7 0 v ANTIMICROBIAL RES ISTANCE IN HUMAN S AN D ANIMALS 79 Frequency of Drug Res istance in Cl inical I so l ates of Salmonel l a spp . from Humans and An imals in the United States , 7 9 Frequency of Drug Res istance in Cl inical I solates of � 2Qli from Humans and Anima l s in the United States , 8 6 E ffect o f Banning the Use o f Subtherapeutic Doses of Antibiotics , 9 0 VI EVI DENCE OF TRANSMISSION OF PATHOGENS O F FARM 99 ORIGIN TO HUMANS Escherichia QQli, 99 Salmonel lae , 102 Other Enteric Pathogens , 107 xi

I EXECUTIVE SUMMARY I n 1 9 8 7 , the Food and Drug Administrat ion asked the I nst itute of Medicine to conduct an independent review o f the human health consequences and the risk assoc iated with the use o f penic i l l in and the tetracycl ines at subtherapeut ic concentrat ions in animal feed . The I nstitute estab l i shed a committee and gave it a t ightly drawn charge : perform " a quantitative risk assessment" o f those consequences--to " assess the adequacy of exist ing human health data and use such data to arrive at an estimate of risk , the bas is of which wil l be j usti fied . " I f compl ete quanti fication o f human hea lth risks was not possible because of inadequac ies of the avai l able data , the committee was to evaluate the sc ient i fic information that had become ava i l able s ince the 1 9 8 0 NRC report of a s imilar investigation and make j udgments about the magnitude of the risks . S ince the introduction of the first ant imicrobials into cl inica l medicine their use has exerted continuing select ive pressure , result ing in an increase in the prevalence of ant imicrobial-resistant strains of both primary pathogens and commensal " opportunistic" bacterial species . Succeed ing generations of ant imicrobial s , often possess ing broader spectra of activity , have compounded the problem . Over the years , medical practice has yielded abundant examples of the emergence to predominance of stra ins of common pathogens that bear res istance ( often encoded on pl asmids ) to one or more antimicrobials . I n view of this , many have speculated about the need to l imit inj udicious and unnecessary prophyl actic and therapeut ic use of antimicrobia l s in humans . The cont inued broad , subtherapeutic use of antimicrob ials in animal feeds has added to the concern that such pract ices may contribute to the emergence of res istant stra ins of bacteria that pose a risk to human health . Initial ly , the committee examined ep idemiologic studies that employed recently devel oped molecular fingerprinting techniques capable of directly l inking , by clonal characteristics of the et iologic agent , human il lness due to a foodborne pathogen ( Salmonel l a ) to the same organism with these same clonal characteristics isolated in the food production chain and back on the farm . Although the committee did l ook at the data ava ilable on other infect ious bacteria than salmonel lae , it was not poss ible to find a substantial body of direct evidence estab l i shing conc lus ively 1

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